Pain is the single greatest cause of disability, and its management remains one of medicine?s foremost challenges. Potent opiates can effectively reduce the severity of pain, thereby diminishing patient suffering. Unfortunately, chronic use of these drugs can be harmful to patients, whether by inadvertent overdosing, unintentional addiction, or abuse resulting from dependency on the euphoric effects of the opiate. The magnitude of this problem as a public health issue has led FDA to require the engineering of abuse-deterrence mechanisms into all new products in this class. The applicants seek to determine the feasibility of developing an abuse-deterrent analgesic which relies on a novel approach to administering an opioid via a transdermal patch. The most common methods of abuse involve either snorting, swallowing or injecting the contents of the product; therefore this patch would contain both a potent opioid agonist and an antagonist. Upon oral, nasal, or intravenous administration of the contents of the product, both agonist and antagonist would become bioavailable, thereby substantially blunting or eliminating opioid-induced euphoria. However, when applied as a skin patch, only the agonist (not the antagonist) would be available for absorption through the skin. The aims of this project are 1) design, synthesis, and evaluation (releasability through hydrolysis) of modified antagonists, 2) design, preparation, and evaluation of transdermal patch containing the opioid drug and modified antagonists, along with patch evaluation, and 3) testing and evaluation of abuse-deterrent properties of the transdermal patch formulations. In short, the above objectives will employ chemical synthesis of the modified antagonists, analysis of quantities of agonist and antagonist released from the patch under the various study conditions, and in vitro human skin permeation studies. Upon successful completion of this work, the applicants anticipate submitting a Phase II grant to move the product into full development under GMP conditions, including studies of product stability, preclinical PK efficacy, product safety, skin tolerance and patch wear. This would position the innovator company to file an IND and proceed with full clinical development. The ultimate goal is regulatory approval and commercialization of this product, thereby providing a completely novel approach to abuse-deterrent management of severe pain. This would directly serve the missions of both the NIH --- ?the application of?.knowledge to enhance health, lengthen life and reduce the burdens of illness and disability? --- and the SBIR --- to ?stimulate technological innovation?, ?meet Federal research and development needs?, and ?increase private-sector commercialization of innovations derived from Federal research and development funding?.